Different HIV-1 strains have different antibody neutralization phenotypes (or CD4-dependencies). However, the molecular mechanisms underlying these differences remain to be elucidated. In this study, we constructed gp120 structural models from the CD4-dependent, neutralization-resistant JR-FL strain and the CD4-independent, neutralization-sensitive R2 strain and carried out several conventional molecular dynamics (MD) simulations and free energy landscape (FEL) constructions. Comparative analyses of the MD simulations and FELs indicated that R2 gp120 had higher global structural flexibility and greater conformational diversity than JR-FL gp120. This provides the preconditions for R2 gp120 to adopt a more open conformation than JR-FL gp120. Essential dynamics (ED) analysis showed that the collective motions of R2 gp120 tend towards an open state while those of JR-FL gp120 tend to retain a closed state. Based on conformational selection theory, R2 gp120's more readily sampled open state makes it more sensitive to neutralizing antibodies (or more CD4-independent) than JR-FL gp120, which may explain why the HIV-1 R2 and JR-FL strains show CD4-independent and -dependent phenotypes, respectively. Our study provides thermodynamic and kinetic insights into the CD4-dependent and -independent molecular mechanisms of HIV-1 gp120 and helps shed light on HIV-1 immune evasion.
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